1. Field of the Invention
The present invention relates to an improved process for etherifying steroids which have a hydroxyl group attached directly to an aromatic ring.
2. Description of the Prior Art
Among conventional processes, the currently most widely used process for etherifying a phenolic hydroxyl group of steroids which have a hydroxyl group attached directly to an aromatic ring is by suspending or dissolving the phenolic hydroxyl group containing steroid into an alkaline aqueous solution, an alcoholic alkaline solution or a mixture thereof, and then adding dialkyl sulfate thereto. However, that process has the disadvantage that when the dialkyl sulfate is added into the high concentration alkaline solution, a reaction of dialkyl sulfate with alkali occurs in preference to the reaction of the dialkyl sulfate with the phenolic hydroxyl group of the steroid. A large amount of an inorganic sulfate is thus formed as a by-product to the reaction, and the desired steroid ether can be obtained in yields of only 50-70% of the theoretical. Even if the alkali and dialkyl sulfate are used in large excess amounts, the yields are still quite low. It has thus been very difficult to industrialize the conventional reaction technique.
After an elaborate study to overcome the above problems, the present inventors have found that steroids which have a hydroxyl group attached directly to an aromatic ring, and dialkyl sulfate are first admixed into a water-alcohol solvent. An alkali is then added thereto to obtain the desired product. This reaction results in improved yields of 70-97%. However, this process still has the following disadvantages:
1. At least 20 equivalents of dialkyl sulfate and alkali for the starting material steroids are necessary to obtain the desired product in such a high yield.
2. The homogeneous reaction is difficult because of the low solubilities of the reactant steroids having a phenolic hydroxyl group. Also, the obtained alkyl ethers in water-alcohol solvent result in a high slurry concentration of the reaction mixture.
3. The maximum purity of the obtained alkyl ethers is 95-97% and a further purification is required.